Results of ECOG Trial EST 1684 demonstrated that adjuvant therapy with recombinant interferon alfa-2b improves both disease-free and overall survival for melanoma patients with a high risk of recurrence. However, the majority of patients in this trial had advanced nodal metastasis; i.e., palpable lymph nodes. Using the technique of lymphatic mapping and sentinel lymph node biopsy, it is now possible to identify very early microscopic nodal metastasis. Using polymerase chain reaction (PCR) technology, it is also possible to detect submicroscopic nodal metastasis. Patients with a single positive lymph node have a much better prognosis than patients with multiple positive nodes, with a 1O year overall survival rate of 40% or better. Although we do not yet know the long-term prognosis of patients with submicroscopic nodal metastasis, it is assumed that it will be better than those with microscopic disease. This patient population is significantly different than those studied in ECOG Trial EST 1684. A significant proportion of these patients can be expected to be cured of their disease by lymphadenectomy alone. Because the toxicity of adjuvant interferon alfa-2b can be significant, it is important to determine whether these subsets of patients benefit from therapy. The central hypothesis of the Sunbelt Melanoma Trial is that regional lymphadenectomy plus adjuvant high dose interferon alfa-2b therapy improves diseasefree and overall survival for melanoma patients with early (sentinel lymph node-only) nodal metastasis compared to lymphadenectomy alone. The study is divided into two parts, designated Protocols A and B. Primary endpoints are disease-free and overall survival. Protocol A is for patients with positive sentinel node(s) detected by histology or immunohistochemistry. Patients with more than one positive sentinel lymph node, any positive non-sentinel lymph node, or any node with extracapsular extension of tumor will receive standard interferon alfa-2b therapy. Three-hundred patients with a single positive sentinel lymph node will be stratified by tumor thickness and randomized to receive lymphadenectomy alone or lymphadenectomy plus interferon alfa-2b therapy. Protocol B is for patients with a sentinel node that is positive only by PCR analysis for tyrosinase MRNA. If the sentinel node is negative for tyrosinase MRNA by PCR analysis, the patients will be followed with no further treatment. If the PCR test is positive for the presence of tyrosinase MRNA, 450 patients will be stratified by tumor thickness and randomized to one of three treatment arms: observation, lymphadenectomy alone, or lymphadenectomy plus interferon alfa-2b therapy. Furthermore, all patients will undergo prospective analysis of peripheral blood by PCR to detect circulating melanoma cells in order to determine the predictive value of this molecular staging test.